Genes of the Major Histocompatibility Complex (MHC) present a paradigm for how selection can act to maintain (or eliminate) adaptively important (or detrimental) genetic diversity in natural populations. The human MHC class I region contains six expressed class I genes, MHC-A, B, C, E, F and G. The Parham lab unexpectedly discovered a seventh class I gene in chimpanzee named Patr-AL because it was most like MHC-A and was identified in the chimpanzee (Pan troglodytes A-like). The Patr-AL gene is linked to Patr-A (chimpanzee ortholog of HLA-A) and found within a unique 125kb block present on only ~50% of MHC haplotypes. Patr-AL encodes a 22m-associated protein that is the only known MHC class I isoform with a basic isoelectric point (8.5). This suggests that Patr-AL has a unique function unlike any known vertebrate MHC class I molecule. Phylogenetic analysis has recently demonstrated that humans have an MHC-AL ortholog, the inactive HLA-Y pseudogene. Very limited sequencing of HLA-Y has identified three alleles. Because each of these alleles contains an independent inactivating mutation, the recent ancestry of this locus likely includes forms that are functional. Also distinguishing the three allelic forms are the presence of segments (in exons) closely related to different modern HLA-A alleles, presumably obtained by recombination, partially due to the strong linkage disequilibrium between HLA-Y and HLA-A. Interestingly, HLA-Y is only present in about 20% of human, mostly non-Caucasian, MHC haplotypes. These observations raise the possibility that HLA-Y has been lost by selection against its unique function, possibly because of an association with disease susceptibility. The fact that HLA-Y is still maintained in the population at a low frequency, however, suggests that it might be beneficial. Because of the presence in HLA-Y of segments closely related to different modern HLA-A alleles, the low frequency of HLA-Y alleles still maintained in the population might contribute to the diversity of the HLA-A locus. These two possibilities are not mutually exclusive. I therefore propose to test the hypothesis that while HLA-Y has been selected against because of its function, it is still maintained at a low frequency in human populations because it is a useful reservoir of diversity. Experiments proposed aim to locate HLA- Y in the MHC, determine if any active forms persist and examine the function of this gene product. To search for ancestral HLA-Y functions, its chimpanzee ortholog, Patr-AL, will also be investigated. This application therefore aims to address the function of the only known basic MHC class I gene product and investigate biological reasons why this gene has decayed in humans. The project proposed in this application presents a very unique opportunity to catch a glimpse of the recent evolution of human immunity in action. Results obtained from this study will help in the understanding of the consequences of MHC variation on the human immune response and in disease resistance and susceptibility. PUBLIC HEALTH RELEVANCE: Major Histocompatibility Complex (MHC) molecules are essential components of the human immune system and have been shown to play a major role in determining disease susceptibilities. By studying these rapidly evolving immune system components in humans and closely related species of primates we will gain new insight and greater understanding of the human immune system and its contribution to human health and survival.